Trisomy 21 is the most frequent human aneuploidy compatible with survival. It occurs in 1 out of 700 live births causing a constellation of effects known as Down syndrome (DS). Significant efforts to establish the genetic control of the many phenotypes of DS have been made using mouse models. HSA21 is homologous with regions on mouse chromosome 10 (MMU10), MMU16, and MMU17. Extensive investigations have been done with Ts65Dn, a mouse model with segmental trisomy at dosage imbalance for about half of the genes on human chromosome 21 (HSA21). Using Cre-lox chromosome engineering, new models of DS will be made for MMU10 regions of conserved synteny with HSA21 including about 50 homologous genes. Quantitative phenotypes for trisomic (Ts2Rhr) and monosomic (Ms2Rhr) mice will be compared to clinical data for human trisomy and segmental monosomy 21. Additionally, Ts2Rhr/Ts65Dn compound transgenic mice will be used to assess the contribution of the MMU10 region in DS phenotypes. The importance of MMU10 will be verified using analysis of variance (ANOVA) and regression with comparisons between the different DS mouse models .